Examining Parvalbumin-Positive Interneuron and Perineuronal Net Expression after Neuregulin-1 Administration for the Treatment of Social Memory Deficits in a Fragile X Syndrome Mouse Model

Abstract

Fragile X Syndrome (FXS) is a genetically inherited neurodevelopmental disorder caused by a mutation in the FMR1 gene. Fmr1 knockout (KO) mice represent a validated model for examining the endophenotypes and neural mechanisms underlying FXS, characterized by deficits in social communication and intellectual ability. Notably, Fmr1 KO mice exhibit a decreased concentration of perineuronal nets (PNNs), extracellular matrix structures crucial for regulating plasticity, within the hippocampal CA2, a region previously established as indispensable for social memory (i.e. the ability to recognize and remember conspecifics) in mice. Previous research showed that Neuregulin-1 (NRG1), a growth factor implicated in the experience-dependent regulation of parvalbumin-positive (PV+) inhibitory interneurons, was sufficient to increase deficient PNN expression in the CA2 of a neurodegenerative mouse model. However, whether NRG1 can similarly increase PNN expression in Fmr1 KO mice and whether PV+ interneuron expression is compromised in the CA2 of Fmr1 KO mice throughout development remains to be elucidated. Given that FXS is speculated to contribute to hyperexcitable neuronal circuits and reductions in inhibitory transmission (termed the “excitatory-inhibitory imbalance theory”), decreased PNN expression in the CA2 could correspond to diminished PV+ cell activity, reflecting reduced inhibitory drive. In the present study, behavioral testing in the form of the direct social interaction test (DSIT), alongside immunohistochemistry and confocal imaging analysis, were performed to precisely quantify the impact of NRG1 administration on social memory ability and the expression of PNNs and PV+ cells in both Fmr1 KO mice and healthy controls in early development and beyond.